Page 1 of 1 Meeting Summary EPA/U.S. Silver Task Force/Zeolite Registrants Meeting October 5, 2010, 10:00 AM to 11:30 AM Room S-8100, 2777 S. Crystal Drive, Arlington, VA 22202 Participants U.S. Silver Task Force/Zeolite Registrants: Joe Hayes, Gary Burin, Erik R. Janus, Erin Tesch, Paul Ford, Javier Takahashi EPA: A. Najm Shamim, Nader Elkassabany, Tim Leighton, Mark Hartman, Seiichi Murasaki, Talia Lindheimer, Abigail Downs, Rebecca von dem Hagen, William Hazel, Tim McMahon, Jonathan Chen, Earl Goad, Jenny Tao, Steven Malish, Jim Breithaupt, Lance Wormell Summary On Tuesday, October 5, 2010, members of AD’s silver registration review team and the silver zeolite work group hosted a meeting withthe US Silver Task Force (STF) zeolite antimicrobial registrants (AgION Technologies, Sinanen Inc., BASF Corporation, and Fuji Chemical). The STF/zeolite antimicrobial registrants requested this meeting to discuss the possibility of bridging available data between the antimicrobial zeolites including silver, zinc, silver zinc and silver copper zeolites, all of which are manufactured from zeolite A, a material widely used in household detergents. During the meeting, the STF/zeolite registrants presented an overview of zeolite A and highlights of a previouslysubmitted white paper on available chemistry and toxicology data for zeolites and zeolitebased antimicrobial products. Next Steps Prior to issuing the data call-ins associated with the silver registration review case, EPA will make a determination on whether or not to bridge available data between the antimicrobial zeolites.

# Zeolite- Based Antimicrobials Chemistry, Toxicology, Exposure Registrants of Zeolite- Based Products on the U.S. Silver Task Force Environmental Protection Agency Meeting

October 5, 2010 Washington, DC

# Items for Discussion Zeolite
• Zeolite structure & chemistry • Zeolite A Antimicrobials • Silver zeolites & 

# silver salts • Elution of metals 

# Toxicity
• Zeolite A • Silver,copper,zinc • Zeolite - based antimicrobials 

# Exposure SummaryAl 3+



# Tetrahedrons

Oxygen Aluminum Silicon Element Symbol

Si 4+

Central (metal) atoms referred to as “T” atoms; structure sometimes called “TO 4 .” Rules : One external cation needed for each Al Two Al may not share an O (Loewenstein) Therefore Al ≤ Si

# Aluminosilicates

Form Type CAS # Structure (example) 

# Phyllo alumino silicates Layered Clays 1302 - 78 - 9, 1318 - 93 - 0, etc. 

# Tecto alumino silicates Cage - like:

All oxygens link two metals Zeolites 1318 - 02 - 1

1344 - 00 - 9 Amorphous alumino silicates Amorphous Silicic acid, sodium aluminum salt; Aluminum sodium dioxido (oxo) silane; etc. Amorphous; anti - caking agents, etc.

# • Over 40 natural minerals

• Numerous synthetic zeolites

• Over 190 possible frameworks 

# Many Zeolites Exist

# Structure of Sodalite Cell

(basic structure of Zeolite A)

Generalized model. Green: aluminum or silicon; yellow: oxygen. Tetrahedrons shown on left, omitted on right. Adsorbed cations and water omitted.

# β-cage (SOD cell)

Link Oxygen) 16

+ 16/2 Oxygen 12 Aluminum 12 Silicon # Element Symbol

# Structure of Zeolite A

Structure of Zeolite A (LTA). Oxygen, adsorbed water, and cations omitted. ( a) SOD sub - structure, with 24 “T” atoms. ( b), ( c), and ( d ): increasingly consolidated structures. Dashed red lines show position of one four-T- atom group in each of the sketches. Pore opening (dotted green arrows) about 4.2 Å dia., opens into 11.4 Å diameter α cavity.

### Largest Application for

Zeolite A (“sodium aluminosilicate”): Softens wash water by ion exchange (Na+ for Ca++ and Mg++) Replaced phosphates (TPP) in powdered detergents Detergent Builders: >>1,000,000 tons/year (1990’s) Antimicrobials: ~100 tons/year 

### Tide Coldwater Powder Detergent Ingredients Ingredients By Prominence Fresh Scent Sodium Aluminosilicate Sodium Carbonate Alkyl Sulfate Water Sodium Sulfate Linear Alkylbenzene Sulfonate Sodium Percarbonate Nonanoyloxybenzenesulfonate Sodium Polyacrylate Polyethylene Glycol 4000 Diethylenetriamine Pentaacetate (Sodium Salt) Fragrance Palmitic Acid Protease Disodium Diaminostilbene Disulfonate FD&C Blue 1 Silicone Sodium Aluminosilicate is an additive which captures hardness from the wash water.

Source: http://www.tide.com/en - US/product/tide - coldwater- powder.jspx 

# Widespread Use in Detergents

# History of Zeolite- Based



# Antimicrobials

• Conceived by Zenji Hagiwara (Japan), early 1980’s

– Patent priority 1/21/1983 (Japan)

– US patents 4,775,585; 4,911,898; and 4,911,899 

## • Development by two Japanese companies, still the only manufacturers, both from zeolite A

– Sinanen (makes its own zeolite)

– Kanebo, now Fuji Chemical (contracts manufacture) 

## • US Registrations from 1990’s

– Kanebo from 7/2/93



### – Sinanen from 5/13/99 

## • Partners for US and European markets:

– Sinanen / AgION

– Kanebo (Fuji) / Ciba (BASF)

# Silver Ion Antimicrobials

• Advantages:

– Silver is found in environment and human body.

– Does not elicit resistance.

– Toxic to prokaryotes, generally inactive against 

## eukaryotes. 

# • Problem:

– Incompatible with organic polymers. 

# • Resolution:

– Use zeolite as an inert, inorganic carrier to put silver ions into organic matrices.

# Why Zeolite A for Antimicrobials?

• Maximal weight capacity (Al:Si = 1:1)

– One exchange cation for each Al 

## • Large cavities (α 11.2 Å; β 6.6 Å)

– 12 cations, 27 H2O per unit 

## • Small window size (4.2 Å)

– Controlled slow rate of elution 

## • Beveled crystal edges

– Good blending in matrix, low abrasion 

## • Simple chemistry, stable quality

– Manmade inorganic material 

## • Benign, ubiquitous, economical

– Widespread use in detergents 

## α β

# Conversion to Antimicrobials

• Production of antimicrobials from zeolite A is a simple soaking process. 

# • Salts of the selected cations (Ag, Zn, Cu, NH 4 

# , etc.) are added to an acidified slurry of zeolite A in deionized water. • When ion exchange (replacing sodium) is complete the slurry is rinsed, filtered, 

# dried, and packaged.

# Discoloration

• Problem :

– Sodium (Na +) in zeolite A may exchange with aqueous H + .

– The resulting alkaline surface environment promotes:



### Ag + 

### + OH - 

### => AgOH AgOH + Ag + 

### => Ag 2 

### O + H + [AgO 2 is brown/black, insoluble] 

### • Techniques to reduce discoloration :

– Low pH during manufacture

– Mask with white pigments

– Using Ag - Cu zeolite for “bluing” [USP 7,645,824 to AgION] 

### • Zn ++ 

### and Cu ++ 

### to limit residual sodium :

– Originally expected to increase efficacy

– Antimicrobial effect << Ag +

– Now used primarily to reduce discoloration

# Silver Zeolites & Silver Salts (Agency Position)
• The ADTC concluded that chemically, zeolite - based silver active ingredients were not similar to salts of silver and hazards would need to be considered separately for each silver compound.

• However, for purposes of hazard characterization and endpoint selection for risk assessments involving elemental silver and silver salts, the ADTC concluded 

## that silver salts can be treated together as a class, based on the knowledge that once internalized to the body, the compound of interest is ionic silver, which is common to the silver salts. Therefore, one 

## toxicology dataset can represent the hazard for the silver salts. [McMahon to Kish/Swindell, 10/20/2004: EPA- HQ - OPP - 2009 - 0011 - 0009; repeated almost verbatim in Chen & Malish thru Petrie/Elkassabany/Cook, 09/15/09: EPA- HQ - OPP - 2009 - 0011 - 0011]

# Silver Zeolites & Silver Salts (Our View)
• The term “zeolite - based silver active ingredients” is incorrect. The active ingredients in zeolite - based antimicrobials are silver (and/or other metal) ions in an inert zeolite A carrier. (See PWP Tables 1 and 6 and product registrations/labels.) 

## • The term “silver compound” is also incorrect. The ions are held to internal zeolite surfaces by 

## electrosorption, not bound into compounds. • Exactly as for silver salts, for zeolite - based silver antimicrobials, “once internalized to the body, the compound of interest is ionic silver, which is common to the silver salts.”

# Silver Zeolites AS Silver Salts (Our argument)


# • Such zeolites may be considered as type of salt, in which the anion is an essentially insoluble crystal. 

# • Cations enter solution through ion exchange, the rate controlled by diffusion (in and out) through the anionic crystal structure. • Zeolites carrying multiple ions may be compared to mixtures of ordinary salts. • The zeolite anion should be regarded as an inert carrier; the carried ions are responsible 

# for all antimicrobial effects.

# Zeolite Antimicrobials as Salts CAS# PC code Wt % (range)

Wt % (typical) 

## Cations*

(typical cell) 

## Anion

(8 cells 

### shown) Ag + Zn ++ Cu ++ Zeolite A (Na - zeolite) 68989 - 22 - 0

--- ---

--- ---

--- ---

--- 

# ++++++ ++++++ Ag zeolite 130328 - 18 - 6

221700 2.5 - 22

3.5 ---

--- --

-- 

# + +++++ ++++++ Ag - Zn zeolite 130328 - 20 - 0

129103 3 - 5?

3.5 6 - 15? 6.5 --

-- 

# + ‡ † 

# ++ ++++++ Ag - Cu zeolite 130238 - 19 - 7

129057 3.5

3.5 ---

--- 6.1 6.1 

# + ‡ † 

# ++ ++++++ Zn zeolite ---

--- ---

--- 14.3 14.3 ---

--- 

## ‡ ‡ ‡ ‡ 

# ++++ * Cations: 

# + Na+, H+, etc.; 

# + Ag+; 

# ‡ Zn++; 

# ‡ Cu++. Not shown: 27 water molecules/cell when fully hydrated.

# Application: Material Preservative

• Zeolite particles blended into polymer matrix (1~3 wt%) • Ag+ eluted only from particles exposed on surface • Typical Ag+ concentration in surface moisture: 5~50 ppb (Photo is actually soap – sorry about the color.)

# Elution of Metals

• Typical Ag content in antimicrobial: 3% or less • Typical Ag - zeolite in final product: 3% or less • Elution only from particles at the surface of the protected material

• Leaching studies on Ag - Zn and Ag - Cu zeolites found ppb water concentrations, well below US drinking water standards

– Leaching depends on surface -to -volume ratio (greater for fibers than for plaques); for fibers silver generally < 20 ppb, Zn difficult to distinguish from background, only copper >100 ppb. [MRID 41615818 & 42032807]


### • FDA-type migration study on 3% of agent (of which 20% = Ag - Zn zeolite) in polyethylene found no detectable silver (<5 ppb) and 

### ca. 100 ppb zinc (significant component in inert ingredients 

## ). [EPA- HQ - OPP - 2009 - 0011 - 0007.2]

# FDA and EPA Regulation of 

# Zeolites in Pesticides and Food

• Allowed as “4A” inerts in FIFRA 25(b) “reduced risk” pesticides [www.epa.gov/opprd001/inerts/section25b_inerts.pdf ]



### • Permitted as inerts in non -food - use pesticides [www.epa.gov/opprd001/inerts/inert_nonfooduse.pdf]

• Exempt from tolerance as inert agricultural pesticide ingredient (diluent, carrier) [40 CFR 180.910]

# FDA Food Contact 

# Notifications for Zeolites
47 Zeolite A in which silver, zinc and ammonium ions have been exchanged for sodium ions. The silver content of the modified zeolite shall not exceed 2.5 percent by weight. Sinanen Company, Ltd. 6/9/2000
134 Sodium zeolite A (CAS Reg. No. 68989 - 22 - 0). PQ Corporation 5/30/2001 193 Silver zinc zeolite, a mixture of silver- magnesium - zinccalcium phosphate sodium alumino silicate, zinc oxide (CAS Reg. No. 1314 - 13 - 2), and hydrotalcite (CAS Reg. No. 12304 - 65 - 3). Kanebo Chemical Industries, Ltd. 3/6/2002 270 A silver- zinc- sodium aluminosilicate zeolite containing up to 2.9 percent by weight of silver and 19 percent by weight of zinc. The finished zeolite will also contain small amounts of calcium metaphosphate, zinc oxide and silica. Kanebo Chemical Industries, Ltd. 12/18/2002
294 Zinc zeolite A (zinc sodium aluminosilicate). Kanebo Chemical Industries, Ltd. 2/13/2003 351 A type of zeolite in which silver, zinc and ammonium ions have been exchanged for sodium ions. The silver content of the modified zeolite shall not exceed 5 percent by weight. AgIon Technologies 10/21/2003 535 A type of zeolite in which silver, copper and ammonium ions have been exchanged for sodium ions. AgIon Technologies 11/11/2005 614 Zeolite Na - P REPLACES FCN #548 Ineos Silicas Group 6/14/2006 697 Zeolite A in which silver and zinc ions have been exchanged for sodium ions. Cosmo Advanced Material Company, Ltd. 4/27/2007 773 Zeolite A (CAS Reg. No. 68989 - 22 - 0) in which silver and ammonium ions have been exchanged for sodium ions. Sinanen Zeomic Company, Ltd. 1/22/2008

# Questions on Zeolite A?

# CEDI/ADI Comparison for Zeolite Na-A as a Food Contact

Substance ZEOLITE Na-A CAS RN or Other ID Code: 068989220 

### Acceptable Daily Intake: 0.2925 mg/kg/day Cumulative Dietary Concentration: 550 ppb Cumulative Estimated Daily Intake: 0.028 mg/kg/day 

### REGNUM: 176.170 (21 CFR) TOX Study Date: 10/26/1982
http://www.fda.gov/Food/FoodIngredientsPackaging/FoodContactSubstancesFCS/CEDIADIDatabase/default.htm

# Toxicity of Zeolite A (Gloxhuber)

Gloxhuber, Ch., et al. , Zeolithe A – A Phosphate Substitute for Detergents: Toxicological Investigation, Fd Chem. Toxic, Vol. 21, No. 2, pp 209 - 220, 1983.

# Metals Used in Zeolite



# Antimicrobials
• Zeolite serves as a convenient carrier 

# for the cations and has no antimicrobial properties 

# • Copper, zinc and silver are cations used in zeolite antimicrobials • Zeolite antimicrobials are typically incorporated into polymers or other hydrophobic organic materials

# Zeolite Antimicrobial



# Toxicity
• The toxicity of zeolite - based 

# antimicrobials is due to the toxicity of the metal ions (silver, zinc or copper) 

# carried by the zeolite • This can be shown by examining the toxicity profiles of silver, zinc and 

# copper and comparing those profiles with available data for zeolite 

# antimicrobials

# Zinc Toxicity

• Zinc is an essential element with an 

# RDA of 2 - 14 mg/person • This compares with the EPA IRIS RfD 

# of 0.3 mg/kg/day (18 mg/person). • Daily intake in US ranges from 5.2 to 16.2 mg/person • Excess zinc intake results in hematological and GI effects

# Copper Toxicity

• US population is exposed to copper 

# from air, water, diet, and contact with soil and consumer products e.g. , 

# doorknobs • RDA for copper is 0.9 mg/person • RfD not established • EPA- quantitative assessment not necessary for copper

# Silver Toxicity

• EPA- no adverse systemic effects after 

# oral or dermal exposure to silver • Laboratory animal studies not relevant 

# for pesticidal risk assessment because EPA risk assessment will be on the basis of argyria seen in human study 

# • 28 - day rat inhalation study to be required by EPA (FWP)

# Zeolite- based Antimicrobial



# Toxicity
• Acute studies available for zeolite 

# antimicrobials generally show no toxicity except for irritation 

# • Other available data include subchronic oral rat and dog, and subchronic dermal rat, multigeneration reproduction, rat 

# teratology, genotoxicity • Subchronic rat and reproduction studies 

# not acknowledged by FWP

# Subchronic Oral Toxicity - Rat

• Dose levels of 1000, 6250 and 12500 ppm 

# (equivalent to 13, 81.25 and 156 mg/kg/day of zinc) of silver zinc zeolite were given to rats in the diet for 90 - days 

# • Hematological effects indicative of microcytic anemia were seen at mid - dose and high dose levels in this study • NOAEL in rat for hematological effects of zinc is 53 mg/kg/day (EPA/635R - 5/002). 

# • Toxicity observed is clearly zinc - relatedDevelopment Toxicityrodent Reproductive

Toxicity Subchronicrodent Subchronicnonrodent Subchronic

dermalrodent Silver zeolite Read across

and/or down Read across

and/or down Read across

and/or down Read across

and/or down Read across

and/or down
Zinc zeolite Read across

and/or down Read across

and/or down Read across

and/or down Read across

and/or down Read across

and/or down Silver copper zeolite Study available Read across and/or down Read across

and/or down Read across

and/or down Study

Available Silver zinc zeolite Read across

and/or down Study available Study available Study

available Read across

and/or down 

# Available Toxicity Studies 

# for Antimicrobial Zeolites

# Exposure to Zeolite



# Antimicrobials
• The use of zeolite antimicrobials as material preservatives poses low exposure potential

– Both indoor and outdoor uses designed to remain in material for its lifetime to the greatest extent possible



# – Migration studies done to support FDA Food Contact Notifications show zeolite itself is not released
• Extremely low levels of Al, Ag and Zn released, if detected (see FCN 351 for silver zinc zeolite)

# Worker Exposure to Zeolite



# Antimicrobials

• Dermal exposure to workers prior to 

# incorporating the antimicrobial is possible; HOWEVER,

– Zeolites would not be absorbed intact

– Metal ions would be poorly absorbed in absence of PPE 

# • Risk to workers or general population should be assessed by comparison of exposure to relevant metal reference dose 

# (as the zeolite is inert)

# Summary

• Zeolite - based antimicrobials consist of Ag+ (and/or other metal) ions (cations) in an inert zeolite carrier framework. • All biological effects are attributable solely to the metal ions (since zeolite is toxicologically inert). 

## • Zeolite - based silver antimicrobials are similar to silver salts, in that they can be “treated together [with the salts] as a class, based on the knowledge that once internalized to the body, the compound of interest is ionic silver.”

– (This applies to zeolite - based antimicrobials with copper and zinc as well.)